Neurosyphilis treatment and material therefor



Patented Sept. 19, 1933 PATENT OFFICE NEUROSYPHILIS TREATMENT AND MATERIAL THEREFOR Paul J. Hanzlik, San Mateo, Calif., assignor to The Board of Trustees of The Leland Stanford Junior University No Drawing. Application March 14, 1932 Serial No. 598,883

Claims.

The invention relates to methods for the treatment of syphilis and prevention of neurosyphilis, as well as to materials for use in such methods. This application is a continuation in part of my goo-pending applications Serial Nos. 436,889 and 485,305, filed March 18, 1930, and September 29, i930, respectively.

It is an object of the invention to provide a method for the treatment of syphilis and prevention of neurosyphilis characterized by the fact that a metallic element, such as bismuth, is caused to enter the brain and cerebrospinal fluid.

It is another object of the invention to provide a material which is more eifective in the control of the late manifestations of syphilis and neurosyphilis than materials heretofore used. 7

It is another object of the invention to enable manufacture of a material of theabove character which will have a uniform and definite bismuth content in anionic form, whereby doses of the same can be properly regulated.

Another object of the invention is to provide a material for treating the aforementioned diseases which can be injected intramuscularly with-.- out undue irritation and other objectionable features.

A further object of the invention is to provide a vehicle for a material of the above mentioned character which is substantially non-irritating and non-toxic, and hence can be employed without discomfort to the patient.

As I have previously related, in the aforemen-v tioned applications, it is an accepted fact that neurosyphilis begins at the time of acute syphilis and hence it is desirable to begin the treatment of neurosyphilis at the time of treating acute syphilis. Further, that while there are'numerous anti-syphilitic drugs in common use, including bismuth compounds, in which the bismuth isin 40 cationic form, these drugs cannot be relied upon so as to permit the entrance of the drug intothe cerebrospinal fluid. In short, these compounds, it has been found, do not enter into the cerebro.-' spinal fluid readily, if at all, and their injection is attended with pain and discomfort.

In general, preliminary treatment of" the patient in order to increase the efficiency of pene tration of these aforementioned compounds is resorted to, but these preliminary treatments are. more or less ineffective. Also, since the vehicles in which these compounds are injected intramuscularly are handled by the body with diniculty, frequently serious or undesirable'consequences result. Often tumors and abscesses have .is present in these preparations in anionic form. to penetrate the central nervous system readily occurred'at the point of injection upon continued use of the aforementioned compounds with the present vehicles.

It will be observed, therefore, that it is advantageous, therapeutically, to obtain an anti-syphilitic drug which is dependably capable of penetrating the central nervous system and entering the cerebrospinal fluid unaided, and which is substantially free of impurities detrimental to such therapeutic use. It is further advantageous to obtain a vehicle for such a drug which is substantially non-irritating and non-toxic", and otherwise unobjectionable.

' In accordance with the present invention, a bismuth compound has been prepared and a vehicle provided therefor having the desirable qualities aforementioned. I have determined that bismuth when present in acid or anionic form is capable of penetrating the brain. Particularly, I have determined that the sodium salt of bismuthic acidNaBiO3, in which bismuth is in anionic form, is capable of entering into the brains of animals. This particular compound, however, is impractical and undesirable for the treatment of humans because insoluble in all or dinary solvents, and, after injection, remains as a relatively unabsorbable depot. Certain relatively soluble'and absorbable bismuth compounds, in which bismuth is present in anionic form, have been prepared and particularly salts of a haloid bismuthous acid, such as iodo-bismuthous acid. Other halogen containing salts such as the chlorand the bromo-bismuthites have been prepared. The term salt as employed herein, is intended to include such inorganic salts as the sodium, calcium and ammonium salts of the iodobismuthous acid, and also the organic salts or esters, such as the acetyl, benzoyl, benzyl, and sulphocyan. Analysis has substantiated the fact that bismuth The preferred material of the invention is sodium iodobismuthite, the preparation of which is relatively simple. The other compounds mentioned can be prepared by a similar process, such changes being made as are within the skill of the chemist making them. By way of example rather,- than by way of limitation, I will detail the preparation of sodium iodobismuthite,-as the effectiveness of th is substance in the treatment of humans has been demonstrated.

This saltpreferably is prepared by the. addition of dry'. sodium iodide to a saturated solution of bismuth chloride or bismuth iodide in a suitable solvent suchas anhydrous ethyl acetate, until the While the reaction proceeds at room temperature I have foundthat heating the mixture on a water bath with a reflux column attached, hastens the reaction and enables a more uniform product to be secured. Thus, for example, a constant rate of, and a more complete reaction is secured as against the indeterminate rate under the fluctuating room temperatures.

When the reaction is complete, insoluble sodium chloride and any excess of unreacted iodide are filtered 0E and the filtrate concentrated to a syrupy mass of crystals. Remaining liquor is filtered off by suitable apparatus such as a Buchner funnel. 4

It,has been my observation that due to the formation of acetic acid, as a result of hydrolysis of the ethyl acetate and because of the presence of hydrochloric acid in the bismuth chloride, im-

' purities such as NaBiLi, HBiIs and HI are possibly present in theproduct obtained in accordance with the several foregoing steps. These, and

. possibly other unidentifiable impurities, make the product containingsuch impurities, when injected into a patient, sufficiently irritating to ren der intramuscular injection of the same objectionable'. I have found that these impurities can be eifectively removed byrepeatedly washing the crystals obtained as above; with a liquid in which the impurities are readily soluble, such as ether.

The analysis of thepurifled crystalsgives the formula NazBiIsAHsQjwith an average bismuth content of 21.9% by analysis. The crystals are monoclinic with afbrilliant red color, and are exclusively or entirely f double refractory, and hence free of those impurities which are known to be singlerefractory; From the results of chemical analysis of these crystals, dried at 45" 0.,

it has been found thatthe sodium iodobismuthite is of uniform composition and that the product represents a single compound containing bism'uth in anionic form consisting of acomplexion composed of iodine andbismuth. This is sustained a by the'results ofpetrographicexamination showing that no other constituent is present in the purified crystalline product. Itis iurther'sustained by the factthat the entity or compound forms the same system: of crystals in different solvents, such as alcohol, water, and ethyl acetate.

In order to,-furtherdemonstrate that the bismuth of my material is in anionic form and that the sodium iodobismuthite is not a common double salt, a test may be made to. determine the manner in which the iodobismuthite ion migrates in solution in an electrolytic cell. In such a test, under suitable conditions, the unchanged red iodobismuthite'ion migrates toward the anode of the cell, and the anode fluid gives the typical chemical reactions for bismuth and iodine, showing the presenceof a complex bismuth-iodine anion. Under the' same conditions, other bismuth compounds previously employed in the treatment of syphilis, such as bismuth salicylate or bismuth sodium tartrate, show migration of bismuth toward the cathode, andthus the bismuth of these products is a cation.

Solvents, beside water and ethylene glycol, for iodobismuthite, are propylene glycol, glycerol, alcohol, and ethylene acetate, butjof these other solvents only the propylene! glycol and glycerol ofier possibilities for human injection.

For purposes-of injecting the. material, sodium iodobismuthite, water and glycerol are not suitable. An equeous solution "cannot be employed aeaaaio tion is objectionable for injection since it results in pain and discomfort for the patient.

I have secured .best results, in injecting the material, sodium iodobismuthite, by the use of ethylene glycol or propylene glycol as the vehicle. The injection of glycol is no more objectionable to the patient than the introduction of the needle alone, the material being very mobile, spreads easily and evenly, is easier to handle, is more antiseptic, and apparently less toxic than glycerol. The use of propylene glycol, while possibly not possessing all the advantages of ethylene glycol, will not possibly give rise to oxalate or the formation of calculi, as may the use of ethylene glycol in very large and toxic doses. The pos-- sible disadvantages of ethylene glycol have been carefully investigated, and while in no way serious, since they do -not occur with therapeutic doses of ethylene glycol used with iodobismuthite, the potentialities are removed by the use of propylene glycol. The'glycols mentioned above have been successfullylused without undue discomfort'to the patient or'without the appearance of systemic toxicity or other undesirable symtoms, as with other vehicles; Such glycols do not I require the-giving of a local anaesthetic at the. time of injection, and are,readily;absorbed by the body. f I

I have foundthat precipitation in the tissues, after injection of iodobismuthite, partly due to. hydrolysis, is prevented byadding an iodide, such as sodium iodide, to eitherofthe'glycol solutions.

Potassiu'miodide can be employed chemically, if

desired, but is objectionable. to the patient because the potassium is morejtoxicythan sodium.

In life experiments on'jguineapigs, the use or 10% sodium iodide with; iodobismuthitein either of the glycols gave some precipitation at. the site of injection, but the'us'e ;ofj1'2 sodiufniodide showed no evidences prpretipip aqn aridwtherea fore 12% sodium.iodidel has'jbeen"'adoptedg'and used successfully on humans. {The finalmaterial,

as prepared and successfully employed-on hi1 mans by intramuscular injection, comprises substantially 12% sodium iodide, substantially. 6%]

sodium iodobismuthite, and substantillyi; 82%v propylene or ethylene glycol.

The penetration of bismuth in the brainbythe use of sodium iodobismuthite in glycol solutions J with or without iodide, has been demonstrated, mainly with guinea pigs and rabbits injected with doses falling within the therape ic range. The

resultssecured diifer from most esults described in literature, the latter having been obtained with toxic and fatal doses of other bismuth products. Of forty-one guinea pigs receiving therapeutic injections over periods ranging from five to thirty-nine days, thirty-eight animals, or

' of from one to seventy-three days, all showed bismuth in the brain, the median being about 0.2 mgm. per 100 grams of brain. The brain content of bismuth noted cannot be due to the blood of the brain, since the latter contains only about 1.24% of its weight of blood.

It was not possible to obtain sufiicient cerebrospinal fluid from the animals for analysis, but the spinal fluid of one rabbit gave a positive test for bismuth. In two moribund patients injected with iodobismuthite, the brain showed the presence of bismuth. Of twenty-four human subjects suffering with cerebrospinal syphilis or dementia praecox, treated in accordance with my invention, twenty-two; or about 92%, showed the presence of bismuth by chemical and spectographic analyses of the cerebrospinal fluid. In six patients, the bismuth was demonstrated in the cerebrospinal fluid at the end of eighteen days after the injection of the first dose of iodobismuthite in a concentration comparable to those secured after dosages necessary for anti-syphilitic action according to Lomholt in the' British Medical Journal, November 16, 1929, page 887. Bismuth was still present in the spinal fluid two weeks after the last dose was given. To compare prior practice to the above results, thirteen out of seventeen cerebrospinal fluids from as' many patients receiving total doses of from 0.2 to 16.9 grams of bismuth in the form of bismuth metal, potassium bismuth tartrate in oil, or bismuth salicylate in oil, in which bismuth is. in

. cationic form, in divided doses injected intramuscularly, showed no bismuth, while two of the four positive tests secured were doubtful.

The product of the present invention has proved efiective in preventing and curing the experimental syphilis of animals and in removin human patients, 2 cc. of either the ethylene or propylene glycol solution of sodium iodobismuthite containing sodium. iodide should be injected intramuscularly, preferably into" the gluteal muscles, twice or thrice weekly, the parts receiving the injection being massaged after each injection and about two days allowed free between injections. Up to ten or twelve successive injections may be given within four weeks as a single course of treatment, and three to four courses with periods of about two weeks rest between courses. Unless salivation or stomatitis develops, the injections may be continued as outlined above. If salivation or stomatitis appears, the injections should be stopped and a short period of recovery allowed. These signs in the mouth are the inevitable results of eiTective bismuth therapy and do not necessarily call for special treatment unless severe.

I claim:

1. In an anti-syphilitic material, a single entity salt comprising a complex ion of iodine and bismuth, the bismuth being in anionic form, said salt having the characteristic of forming exclusively double refractory crystals.

2. In an anti-syphilitic material for intramuscular injection, a salt containing bismuth in anionic form, together witha non-toxic glycol.

3. In an anti-syphilitic material adapted to be injected intramuscularly and substantially free of impurities detrimental to such use, sodium iodobismuthite, the bismuth therein being in anionic form, together with a non-toxic glycol.

4. A material suitable for pharmacological and therapeutic use and substantially free of impurities detrimental to such use, said material comprising a compound containing bismuth in anionic form; said compound constituting a comtoxic glycol and substantially 12% sodium iodide.

PAUL J HANZLIK. 

